Field of the Invention
The invention relates to the treatment of cancer. More particularly, the invention relates to the treatment of prostate cancer.
Summary of the Related Art
As the most common malignancy in US males, prostate cancer remains a challenging disease. In contrast to other human cancers, it is exquisitely dependent on androgenic steroids that exert their biological effects through the androgen receptor (AR)1, 2.
The classical model for AR activation involves a conformational change induced by ligand binding, enhanced nuclear translocation, and binding to the androgen-responsive elements in the proximal promoters or distal enhancers of target genes to regulate transcription3. AR-regulated genes are essential for prostate tumor cell growth, invasion and metastasis2, 3. More importantly, recent studies indicate that AR binding dynamics to chromatin vary in prostate cancer cells, depending on cellular context, producing different effects on gene expression in different cases4-6. Therefore, it is critically important to fully understand the molecular mechanisms of AR-mediated transcription, especially those that can be targeted by new drugs.
The first line treatments for patients with advanced prostate cancer are androgen-deprivation therapies that suppress the AR signaling by either inhibiting the androgen-synthetic pathway or antagonizing AR function2. Despite strong responses to androgen-deprivation therapies, patients often relapse with a more aggressive, therapy-resistant form of the disease referred to as castration refractory prostate cancer (CRPC)7, 8. Recent studies showed that most of CRPC tumor cells continue to utilize their endogenous androgen signaling system to drive their growth through restoration of AR function9-11. The mechanisms of AR reactivation include AR gene amplification, ligand-independent transactivation of AR, or activation of intracellular androgen synthesis12-14. Novel anti-androgen therapeutic agents are being developed to treat CRPC, including a new potent testosterone-synthesis inhibitor (abiraterone)15, 16 and a high-affinity anti-AR drug (MDV-3100, a.k.a. enzalutamide)17, 18. Although clinical studies showed that these drugs confer survival advantage13, 19-21, the CRPC still remains far from being cured and requires new effective treatments after the acquisition of resistance to these drugs. All the existing methods for blocking androgen signaling rely on inhibiting the production of the ligand or the ligand-receptor association, which can be overcome in cancers by multiple mechanisms of AR reactivation. Several novel anti-AR drugs have recently been developed to block the AR signaling by inducing AR protein degradation22-24. Recent studies have indicated, however, that AR not only induces certain cancer-promoting genes but also represses other genes that are involved in androgen synthesis, DNA synthesis and proliferation25. Activation of the latter genes by blocking all the effects of AR or by inducing AR degradation may stimulate the transition of PCa cells from an androgen-dependent (AD) to an androgen-independent (AI) state.
There is therefore, a need to develop a strategy targeting other molecules that potentiate AR-mediated transcription to block the hyperactive androgen signaling and to extend the effectiveness of hormone therapies in prostate cancer patients. In particular, there is a need to develop a strategy for inhibiting AR-mediated induction of transcription but not the repression of transcription by AR.